6-fluoro steroids



- o w l 8,491 Patented Juni fi 1958 2,838,491 lower alkyl radical, R is hydrogen or an acyl radical of @FLUORO STEROIDS an organic carboxylic acid, preferably a hydrocarbon Milt E, H Kalamazoo, John Babcock, portage carboxylic acid, containing from one to twelve carbon Township, Kalamazoo County, and I Allan Campbell, atoms, inclusive, and X represents a carbonyl radical John A. Hogg, and Raymond L. Pederson, Kalamazoo, C=O) or a hydroxymethylene radical CHOH). Mich flssiglwl's The pj p y, Kalamazoo, 5 The term lower alkyl radical, as used herein, refers Mich a corporation of Michigan to an alkyl radical of from one to three carbon atoms, 0 Drawillg- Application February 19, 1953 inclusive, e. g., methyl, ethyl, propyl, and isopropyl.

Sena! 716,016 It is an object of the instant invention to provide novel 13 Claims. (Cl. 260-2395) The present invention relates to new 6aand 6fi-fluorin- 1 hydrocarbon-4-androsten-3-ones V and the 17-acylates a'ted steroids and is more particularly concerned with thereof, for example, 6-fluoro-11/3-hydroxy-17a-(a-meth- -fl y my 17a lower alkenyl allyl)testosterones, 6-fluoro-1lp-hydroxy-17a-(a-methalhydrocarbon 4 androsten-3-ones and the 17-acylates 1 1 19mortestostemnes, 11- .17 f thereof, for example, 6-fluoro-1lB,17/3-d1hydroxy-17a-(oc' 15 allyl)testosterones, 6-fluoro-l1-keto-l7a-(a-metha11yD- methallyl) 4 andmsten'3'ones [6'fluoro'l flq l9-nortestosterones and the l7-acylates thereof and novel (a'methauyl)testosterones], 6fluoro'llfil7p'dlhy' intermediates and methods in the production thereof. d 17"("methany1)'l9'nor4'andmsten'3Ones Other objects of this invention will be apparent to those fluoro 116 hydroxy 17cc (a methallyl) 19 nor .v tcstbstemnes]; 6 fluom nflhydmxynw(a methallyl) 2O skilled in the art to WhlCh this invention pertains.

4-androstene-3,11-diones [6-fiuoro-11-keto-17a-(a-meth- The novel Products of thls mvemlon allyl)testosterones], 6-fiuoro-17B-hydroxy-17o-(a-methpoEmds of Formula I P useful fherapeunc If P- allyl)-19nor-4-androstene-3,1l-diones [6-fluoro-1l-ketoewes as orally and parenterlly actW-e progeslatlonal 17u-(a-methallyD-l9nortestosterones], the l7-iacylates t T y fi Secretion of gonadotropms and thereof and novel steroid intermediates and methods used thus regulate Ovulatloll and endomemal and Placental in tha rc arati n th f, development and, particularly when used in conjunction The novel end product compounds of this invention with estrogens, e. g., ethinylestradiol and/or androgens,

are represented by the formula: e. g., Halotestin (9a fluoro-l lp-hydroxy-17-methyl-.

CH5 R1 testosterone), reduce fertility and constitute effective OR: therapy for dysmenorrhea, amenorrhea, endometriosis,

I threatened abortion and related gynocological disorders.

Administration of these steroids can be in conventional R I dosage forms such as pills, tablets, capsules, syrups or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for inject 0: i able products. Microcrystalline aqueous suspensions or oil solutions can be prepared for parenteral dosage.

1 3 I The novel steroids of Formulae Ia, lb, 10, and Id, can

wherein R is methyl or hydrogen, R is hydrogen or a 40. be prepared according to the following reaction sequence:

CH1 7 CH! Id In wherein R and R have the same meaning as previously given, Ac is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, and R is an alkylenegroup which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, and which preferably contains less than nine carbon atoms. I a

One aspect of the process of the present invention corn prises treating compounds ofthe type represented by Formula II, for example, 6-tluoro-llB-hydroxyl-androstene-3,17-diones and 6-fluoro1lfl-hydroxy-l9-nor-4-androstene-3,17-diones with a secondary amine such as pyrrolidine, to obtain the compounds of Formula III, for example, 6-fiuoro- 1 1/8-hydroxy-3-(N-pyrr olidinyl)-3,S-androstadien-l7-one and 6-fiuoro-l1fl-hydroxy-3-(N-pyrrolidinyl)-l9-nor-3,5-androstadien-l7one. Other secondary amines and particularly secondary cyclic'all-zylene amines, such as piperidine, C-alkyl substituted piperidines, e. g., 2,4-dirnethylpyrrolidine, 3-isopropylpyrrolidine, 3,3-dimethylpyrrolidine, and the like, are suitable to convert the compounds of Formula II into the corresponding 3- enamine compounds of Formula III.

The thus-obtained compounds of Formula III areithen treated. with a Grignard reagent, for example, 2-butenylmagnesium bromide (or chloride) to add the side chain at the Uni-position. The Grignard reagent is then decomposed using procedures well-known in the art. Preferably, aqueous ammonium chloride or water is used to decompose the Grignard reagent. Following the Grignard reagent decomposition, the S-enamine group is removed by hydrolysis. The hydrolysis of the 3-enamine group is preferably carried out using a buffered solution, such as a solution containing sodium acetate, water, glacial acetic and methanol. Alternatively, the S-enamine group is l1y drolyzed using mildly alkaline conditions, such as a so dium acetate solution. The. compounds of Formula Ia,

for example, 6 fiuoro 11/8 hydroxy-l7a-(tz-rnethallyl) testosterones and 6-fluoro-l1/3-hydroxy-l7a-(m-methallyD- 19-nortestosterones are then recovered from the solution used to hydrolyze the 3enarnine fgroup'according to procedures well-known in the art, such as by extraction with water-immiscible solvents, e. g., methylene chloride, ether,

benzene, or the like, followed by chromatography.

Other Grignard reagents, for example, allylmagnesium bromide (or chloride), Z-pentenylmagnesium bromide (or chloride), Z-hexenylmagnesium bromide (or chloride) and 2-isohexenylmagnesium bromide are substituted for the v1 Z-butenylrnagnesiurn bromide disclosed above to prepare other compounds represented by Formula Ia,.for example, 6-fluoro-1lfl-hydroxy-17wallyltestosteronc and 6-fluoro- 115 hydroxy-l7a-allyl-19-nortestosterone, 6-fluoro-1 1/3- hydroxy 17a (or-ethallyDtestosterone and 6fiuoro-ll[3-.

mixtures. Thus, butenylmagnesium bromide exists as a mixture of crotylmagnesium bromide (Z-butenylmagnes in brol'nide) and a-methallylmagnesium bromide. Accordingly, the Grignard reagents named above are to be understood as consisting of the equilibrium mixtures.

The l7-acylates represented by Formula 112, for example, the l7-acylatcs of 6-fiuoro-llfl-hydroxy-U -(amethallyDtestosterone and 6-fiuoro-l l fi-hydroxyl 7a(amethallyl)'l9-nortestosteronc are obtained by allowing the compounds of Formula Ia to react with the anhydride of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, for example, a saturated straight-chain aliphatic acid, e. g., acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, a cycloaliphatic saturated acid, e. g., cyclohexanecarboxylic, an alkaryl acid, e. g., pionic, 0-, m-, and p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e. g., sodium, salts), e. g., succinic, adipic, a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, cinnamic, dibasic unsaturated acids (which can be converted into watersoluble, e. g., sodium, salts), e. g., maleic and citraconic. Another aspect of the present invention comprises treating the compounds of Formula Ia, for example, 6- tluoro 11B,17fl-dihydroxy-l7a-(a-methallyl)-4-androsten- 3-one and 6-lluoro-llfi,l7/3-dihydroxy-17a-(a-methallyl)- l9-nor-4-androstene-3-one with an oxidizing agent, for example, chromic acid, potassium dichromate or sodium dichromate, to obtain the compounds of Formula Ic, for

xample, 6 lluoro 17,3-hydroxy-l7a-(c-methaIIyD-4-androstene-3,ll-dione and 6 fiuoro 17B hydroxy-l7a-(amethallyD-lQ-nor 4 andostene-3,l l-dionc, respectively. The oxidation can be carried out by a variety of methods, such as, for example, by oxidizing the compounds of Formula la in acetic acid solution with chromic anhydride or sodium dichromate, or by oxidizing with chromic anhydride in the presence of pyridine. At the conclusion of the desired oxidation reaction, the excess chromic acid is generally destroyed by the addition of methyl alcohol, ethyl alcohol, and the like. Thereafter, the resulting 11- keto compounds of Formula Ic are recovered by conventional means, such as by crystallization, extraction with water-immiscible solvents, e. g., methylene chloride, ether, benzene, toluene, or the like, or by chromatography.

The l7-acylates represented by Formula Id, for example, the l7-acylates of 6-fiuoro-ll-keto-17a-(a-meth allyl)testosterone and 6-lluoro1l-keto-l7a-(a-methallyl)- l9-nortestosterone are obtained by allowing the compounds of Formula Ic to react with the anhydride of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, for example, a saturated straight-chain aliphatic acid, e. g., acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, a cycloaliphatic saturated acid, e. g., cyclohexanecarboxylic, an alkaryl acid, e. g., benzoic, phenylacetic, Z-phenylpropionic, o-, m-, and p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e. g., sodium, salts), e. g., succinic,

enzoic, phenylacetic, 2-phenylpro- PREPARATION 1 A. 6fl-flz10r0-5 a,] 1 fi-dihydroxyandrostane-3,1 7-rli0ne Three grams of 5a,6a-epoxy-llB-hydroxyandrostane-S, 17-dione 3,17-bis-(ethylene ketal), prepared according to the procedure disclosed in copending application Serial No. 661,626, filed May 27, 1957, in 25 milliliters of methylene chloride contained in a polyethylene bottle is treated with nine milliliters of 48 percent hydrofluoric acid. The reaction mixture thus obtained is stirred at room temperature for several hours and then cautiously poured into a mixture of 45 milliliters of methylene chloride and fifty milliliters of ice cold 1.5 molar aqueous sodium carbonate solution and stirred with caution. The mixture is exhaustively extracted with methylene chloride and the methylene chloride solution is 'washed with water and dried over sodium sulfate. Evaporation of the methylene chloride gives a residue containing 6 8-fiuoro- 5 1,1 1 B-dihydrQXyandrostane-S,l7-dione.

B. 6 a-fluoro-I 1,B-hydroxy-4-andr0stene-3,1 7-di0ne,

The residue containing 6(3-fiuoro-5a,llp-dihydroxyandrostane-3,l7-dione produced in Preparation 1A, is mixed in 200 milliliters'of chloroform and seven milliliters of ethyl alcohol and treated with anhydrous hydrogen chloride gas, whilst maintaining the temperature at approximately from minus five to minus ten degrees centigrade. The solution thus obtained is washed with successive portions of water, aqueous sodium bicarbonate solution and water, driedover sodium sulfate, concentrated and chromatographed over 75 grams of activated alumina. The chromatographic column is eluted With Skellysolve B hexanes plus increasing proportions of acetone from two to fifty percent and collected in fifty milliliter fractions. Fractions-8 through 19 are combined and-the solvent removed by evaporation leaving a residue. The residue is recrystallized'from' methylene chloride-hexane to give 6a-fluoro-1lp-hydroxy-4-androstene- 3,17-dione, a crystalline solid.

PREPARATION 2 A. 19-n0r-5-andr0stene-3,11,1 7-tri0ne 3,17-bis-(ethylene ketal) A mixture of five grams of l9-nor-4-androstene-3,ll, l7-trione (U. S. Patent 2,757,186), 250 milliliters of benzene, twenty milliliters of ethylene glycol and 150 milligrams of p-toluenesulfonic acid is vigorously stirred and heated at reflux under a water trap until thereaction is substantially complete. The reaction mixture is cooled, washed with five percent aqueous sodium carbonate solution and water and dried over sodium sulfate. Evaporation of the solvent gives a crude residue of 19-nor-5- androstene-3,11,17-trione 3,17-bis-(ethylene ketal).

B. I ]/3-hydr0xy-19-n0r-5-andr0stene-3J7-di0ne 3,17-bis- (ethylene ketal) The total crude residue obtained in Preparation 2A, is dissolved in fifty milliliters of tetrahydrofuran and added with stirring over approximately a five minute period, under nitrogen, to a mixture of two grams of lithium aluminum hydride and 100 milliliters of anhy- The mixture is stirred at room temperature j for 15 minutes and, whilst ice cooling, carefully treated with' twenty milliliters of water.. The mixture'is then di- 75 drous ether.

luted with 206 milliliters of ether, stirred and filtered to move inorganic solids. The filtrate is Washed with three fifty milliliter portions of Water, dried over sodium sulfate, and the mixture taken to dryness. The residue is recrystallized from ether to give llfl-hydroxy-lQ-nor-S-f androstene-3,17-dione 3,17-bis-(ethylene ketal), a crystal'-- line solid.

C. 5 a,6a-ep0xy-1 1B-hydroxy-I9-norandrostane-3J 7-41-0712 3,] 7-bis-( ethylene ketal) A mixture of two grams of 1 1fl-hydroxy-19-nor-5- androstene-3,l7-dione 3,17-bis-(ethylene ketal), forty milliliters of chloroform and 0.4 gram of sodium acetate is cooled in an ice-water bath and treated with fourmilliliters of forty percent peracetic acid. The cooled mixture is stirred vigorously for about two hours. The cold bath is then removed and the mixture is stirred with forty milliliters of saturated aqueous sodium bicarbonate solu-- tion for approximately one hour and upon being allowed to stand layer separation occurs. The chloroform layer is separated, washed twice with water, dried over sodium sulfate and the solvent removed by distillation. The residue is recrystallized from ether to give 5a,6a-epoxy- 1 lp-hydroxy-l9-norandrostane-3,l7-dione 3, l7-bis-(ethylene ketal) a crystalline solid.

one

A mixture of 1.7 grams of 5a,6 x -epoxy-l'1fl-hydroxy-* l9'-norandrostane-3, l7-dione 3,l7-bis-( ethylene ketal) and sixteen milliliters of methylene. chloride in a poly ethylene bottle is treated with six milliliters of 48 percent" hydrogen fluoride and stirred vigorously at room ternperature for several hours. The reaction mixture is carefully treated with a' solution of ten grams of sodium.

bicarbonate in 125 milliliters of water and extracted "with- The extractris washed with water,.-

methylene chloride. dried over sodium sulfate, and the solvent removed by distillation.

methylene chloride and chromatographed over fifty grams. of Florisil (synthetic magnesium silicate), followed by elution of the column using forty milliliter fractions of. Skellysolve B hexanes plus increasing proportions "of acetone from one to fifty percent. The desired 6fi-fluoro- 5a,1lfi-dihydroxy-19-norandrostane-3,17-dione is eluted first and the solvent is removed by evaporation.

One gram of 6,9-fluoro-5oa1lp-dihydroxy-19 norandrostane-3,17-dione, eighty milliliters of chloroform and one milliliter of ethanol is cooled to approximately minus ten degrees Centigrade and dry hydrogen chloride is passed through the mixture for several hours while allowing the temperature of the solution to warm to approximately zero degrees centigrade. The thus-obtained solution is diluted with milliliters of chloroform,.washed with successive portions of Water, aqueous sodium, bi-

carbonate solution, and water and dried over' sodium sulfate. The solvent is removed by distillation and the residue crystallized from acetone-Skellysolve B hex-- anes to give 6at-fluoro-1lp-hydroxy-19 nor-4=androstene- 3,17-dione, a crystalline solid.

EXAMPLE 1 tadien-17-0ne A mixture of 2.5 grams of fiu-fluoro-l1 3-hydroxy-4 androstene-3,17-dione in twenty milliliters-of methanol is heated to nearthe boiling point, cooled slightly and treated with 1.3 milliliters of pyrrolidine. "The flask is. scratched with a glass, rod to induce. crystallization; The reaction mixture is allowed to coolto room temperature and is then refrigerated at approximately ze ro;degrees centigrade for one hour. The precipitate of 64111616- The residue which contains' 6p-fiuoro-5a',1 13- dihydroxy-l9-norandrostane 3,17-dione is dissolved in 115-hydroxy-3-(N-pyrrolidinyl) 3,5 androstadien-17- one thusobtained is collected by filtration, washed with methanol and dried.

In the same manner as shown above, treating 65-fiuoro- I-hydroxy-4-androstene-3,17-dione with pyrrolidine is productive of 6-fluoro-115-hydroxy-3-(N-pyrrolidinyl)- 3,5-androstadien-17-one.

A solution of 0.100 mole of Z-butenylmagnesium bromide-in thirty milliliters of diethyl ether is prepared according to the method of Young and Roberts, J. Am. Chem. Soc. 68, 1474 (1946), and is stirred under a nitrogen atmosphere while a solution of 3.73 grams of 6-fluoro- 115-hydroxy 3 (N-pyrrolidinyl)-3,5-androstadien-17- one in fifty milliliters of tetrahydrofuran is added over a period of ten minutes. The mixture is distilled until the vapor temperature above the reaction mixture reaches 55 degrees centigrade and then heated at reflux for approximately four hours. The mixture is poured carefully with stirring into iced ammonium chloride solution and the resulting mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and the solvent removed at room temperature or below under diminished pressure leaving a residue. The thus obtained residue is heated at reilux for several hours in a buttered solution of six grams of sodium acetate, six milliliters of water, four milliliters of glacial acetic acid, and forty milliliters of methanol. This mixture is then diluted with water and extracted with ether. The ether extract is washed with water, dilute aqueous sodium carbonate, and water, then is dried over anhydrous sodium sulfate and evaporated to dryness, giving a crude product which is dissolved in methylene chloride and chromatographed over 100 grams of Florisil (synthetic magnesium silicate). The chromatogram column is eluted with Skellysolve B hexanes containing increasing proportions of acetone from one totfifty percent by volume. The eluted fractions are examined by infrared absorption analysis and those fractions which show no C-17 carbonyl absorption are combined and crystallized from acetone-hexane mixture to give 6iz-fluoro-115,175-dihydroxy-17m-(oz-methallyl)-4- androsten-B-one [6a fiUOt'O-llfl-hYdI'OXY-l'loc-(or-methallyl)v testosterone]. 65-fluoro-115,175-dihydroxy-17a-(amethallyl)-4-androsten-3-one is present in the crystallization mother liquors, and can be isolated by additional chromatography followed by crystallization from acetonehexane mixture.

In the manner shown in Example 1B, treating 6-fiuoro- 115-hydroxy 3 (N-pyrrolidinyl)-3,5-androstadien-17- one with allylmagnesium bromide and hydrolyzing the product in a buffered mixture is productive of 6-i1uoro- 1l5-hydroxy-17a-allyltestosterone. Similarly, 6-fiuoro- 1 15-hydroxy-17a-(e-ethallyl) testosterone, 6-fluoro-115- hydroxy-17a-(ot-propallyl)testosterone, and 6-fiuor0-115- hydroxy-l7a-(u isopropallyl)testosterone, are prepared by allowing 6-fiuoro-115-hydroxy-3-(l l-pyrrolidinyl)-3,5-

androstadien-17-one to react with Z-pentenylmagnesium bromide, 2-hexenylrnagnesium bromide or Z-isohexenylmagnesium bromide, respectively, and hydrolyzing the enamines as shown in Example 113. Allylmagnesium bromide is obtained following the procedure of Young andRoberts, J. Am. Chem. Soc..68, 1474 (1946) for the preparation of Z-butenylmagnesium bromide but substituting allyl bromide for 2-butenyl bromide. Similarly, Z-pentenylmagnesiIJm bromide and 2-hexenylmagnesium bromide are prepared from 1-bromo-2-pentene and l-bronio-Z-hexene [Young, Richards and Azorlosa, J. Am. Chem. Soc. 61, 3070 (1939)], and 2-isohexenylmagnesium bromide is prepared from 1-bromo-4-methy1- Chirnie, r10] 9, 412, 42 1 6-flu0r0-115,1 -dihydroxy-I 7a-(a-methallyl) 4-midr0sten-3-0ne 17-pr0pi0nate A solution containing one gram of 6u-flUO10-11B,17fidihydroxy-17a-(a-rnethally1)-4-androsten-3-one in nine milliliters of propionic anhydride is heated at a temperature of approximately to degrees centigrade until the reaction is substantially complete. The unreacted propionic anhydride is then removed by distilling the reaction mixture under reduced pressure and the residue is recrystallized several times from aqueous methanol to give Ge-fluoro-l15,175-dihydroxy-17u-(oz-methallyl)-4-androsten-3-one 17-propionate. Treating 65-fiuore-115,175-dihydroxy-17a-(a-methallyl) 4 androsten- 3-one with propionic anhydride as above is productive of 65-fiuoro-1 15,175-dihydroxy-17a-(a-methallyl)-4-androsten-3-one l7-propionate.

In the same manner shown above 6 fiuoro 115,175- dihydroxy 17cc (a methallyl) 4 androsten 3 one 17 cyclopentylpropionate, 6 fluoro 115,175 dihydroxy 17a (a methyllyl) 4 androstcn 3 one 17 acetate, 6 fluoro 115,175 dihydroxy 17a (e:- methallyl) 4 androsten 3 one 17 butyrate, 6- fiuoro 115,175 dihydroxy 17cc (a methallyl) 4- androsten 3 one 17 valerate, 6 fluoro 115,175 dihydroxy 17a (a methallyl) 4 androsten 3 one 17 hexanoate, 6 fluoro 115,175 dihydroxy 17:- (a methallyl) 4 androstcn 3 one 17 laurate, 6- fiuoro 115,175 dihydroxy 17a (a methallyl) 4- androsten 3 one 17 trimethylacetnte, 6 fluoro- 115,175 dihydroxy 17a (a methallyl) 4 androsten 3 one 17 isobutyrate, 6 fluoro 115,175 dihydroxy 17cc (u methallyl) 4 androsten 3 one 17 isovalerate, 6- fluoro 115,175 dihydroxy 17- (a methallyl) 4 androsten 3 one 17 cyclohexanecarboxylate, 6 fluoro 115,175 dihydroxy 17a (amethallyl) 4 androsten 3 one 17 benzoate, 6- fluoro 115,175 dihydroxy 1704 (a methallyl) 4- androsten 3 one 17 phenylacetate, 6 fiuoro 115, 175 dihydroxy 17a (a methallyl) 4 androsten- 3 one 17 (5 phenylpropionate), 6 tluoro 115,175- dihydroxy 17a (a methallyl) 4 androsten 3 one 17 (o-, m-, p toluate), 6 fluoro 115,175 dihydroxy- 17o: (a methallyl) 4 androsten 3 one 17 hemisuccinate, 6 fluoro 115,175 dihydroxy 17a (amethallyl) 4 androsten 3 one 17 hemiadipate, 6- fiuoro 115,175 dihydroxy (0c methallyl) 4- androsten 3 one 17 acrylate, 6 fluoro 115,175- dihydroxy 17a (0c methallyl) 4 androsten 3 one 17 crotonate, 6 fluoro 115,175 dihydroxy 17a- (0: methallyl) 4 androsten 3 one 17 undccylenate, 6 fluoro 115,175 dihydroxy 17a (a methallyl)- 4 androsten 3 one 17 propiolate, 6 fiuoro 1.15,

dihydroxy 17a (a methallyl) 4 androsten- 3 one 17 cinnarnate, 6 fluoro 115,175 dihydroxy- 17cc (cc methallyl) 4 androsten 3 one 17 maleate, and 6 fluoro 115,175 dihydroxy 17a (a methallyl) 4 androsten 3 one 17 eitraconate are prepared by dissolving 6 fiuoro 115,175 dihydroxy 17a (amethallyl) 4 androsten 3 one in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated in accordance with the procedure above and recrystallized to give the 6 fiuoro 115,175 dihydroxy 17a (amethallyl) 4 androsten 3 one 17 acylate. If the corresponding acid anhydride is solid, an inert solvent such as toluene, xylene, or dioxane can be added to eifcct solution and to provide a liquid esterification reaction medium.

The 17 propionatcs of 6 fiuoro 115,175 dihydroxy 17a allyl 4 'mdrosten 3 one, 6 fluorol15,175 dihydroxy 17c: (a ethallyl) 4 androsten- 3 one, 6 fluoro 115,175 dihydroxy 17a (upropallyl) 4 androsten 3 one, and 6 fluoro 115, 175 :dihydroxy 17a (o isopropallyl) 4 androsten- 3 one are obtained in the same manner as in Example lC by treating the corresponding steroid with propionic anhydride. Other 17 acylates of 6 fluoro 115,175- dihy-droxy 17a allyl 4 androsten 3 one, 6 fluoro- 115,175 dihydroxy 17a (a ethallyl) 4 androsten- 3 one, 6 fiuoro 115,175 dihydroxy 17a (apropallyl) 4 androsten 3 one and'6 fluoro 115, 175 dihydroxy 17cc (u isopropallyl) 4 androsten- 3'- one are produced in the same mmaner as in Example 1C by dissolving 6 fluoro 115,175 dihydroxy 17aallyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17a (cc ethallyl) 4 androsten 3 one, 6- fluoro 115,175 dihydroxy 17a (a propallyl) 4- androsten 3 one or 6 fiuoro 115,175 dihydroxy- 17a. (a isopropallyl) 4 androsten 3 one in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated and crystallized in accordance with the procedure of Example 1C.

EXAMPLE 2 In the same manner shown in Example 1A, treating 6ozfluoro 115 hydroxy 19 nor 4-- androstene 3,17- dione or 65 fluoro 115 hydroxy 19 nor 4 androstene 3,17 dione with pyrrolidine is productive of 6 fluoro 115 hydroxy 3 (N pyrrolidinyl) 19- nor 3,5 androstadien 17 one.

B. 6-fluor0-115,1 75-dihydroxy-1 7 aa-methallyl 1 9- nor-4-andr0sten-3-0ne In the same manner shown in Example 1B, treating 6 fluoro 115 hydroxy 3 (N pyrrolidinyl) 19- nor 3,5 androstadien 17 one with 2 butenylmagnesium bromide, hydrolyzing the Grignard reaction mixture with aqueous ammonium chloride, and hydrolyzing the resulting enamine with a mixture of sodium acetate, acetic acid, water and methanol is productive of 6afluoro 115,175 dihydroxy 17a (c methallyl) 19- nor 4 androsten 3 one and 65 fluoro 115,175- dihydroxy 17a (a methallyl) 19 nor 4 androsten 3 one. Substituting allylmagnesium bromide, 2- pentenylmagnesium bromide, 2 hexenylmagnesium bromide, or 2 isohexeneylmagnesium bromide for 2 butenylmagnesium bromide in the above process is productive of the corresponding 6 fluoro 115,175 dihydroxy- 17cc allyl 19 nor 4 androsten 3 one, 6 fluoro- 115,175 dihydroxy 17a (a ethallyl) 19 nor 4- androsten 3 one, 6 fluoro 115,175 dihydroxy 17- (a propallyl) 19 nor 4 androsten 3 one and 6 fluoro 115,175 dihydroxy 17a (a isopropallyl)- l9 nor 4 androsten 3 one.

In the same manner shown in Example 10, treating 6 fluoro 115,175 dihydroxy 17a (a methallyl)- 19 nor 4 androsten 3 one with propionic anhydride is productive of 6 fiuoro 115,175 --dihydroxy 170L- (0: methallyl) 19 nor 4 androsten 3 one 17- propionate. a

In a like manner other 17-acylates are prepared by dissolving 6-fiuoro-115,175-dihydroxy-17a-(a-methallyl)- l9-nor-4-androsten-3-one in the appropriate acid anhydride, heating, for example, at between 100 and 150 degrees centigrade and isolating the product as shown in Example 1C.

'The 17-propionates of 6-fluoro-115,175-dihydroxy- 17a-allyl-19-nor-4-androsten-3-one, 6-fluoro-115,l75-didroxy-17a-(u-etha1lyl)-l9-nor-4 androsten-3-one, 6-fluoro-115,175-dihydroxy 17cc (oz-propallyl)-19-nor-4-androsten-3-one, and 6-fluoro-115,l75-dihydroxy-17a-(aisopropallyl)-19-nor-4-androsten-3-one are obtained in twenty milliliters of water.

the same manner as in Example 1C by treating the corresponding steroid with propionic anhydride. Other 17- acylates of 6-fluoro-115,-175-dihydroxy-17u-allyl-19 nor- 4-androsten-3-one, 6-fluoro-l15,l75-dihydroxy-17a-(uethallyl) -19-nor-4-androsten-3-one, 6-fluor0-115,175-dihydroxy-17a-(a-propallyl)-19-nor-4-androsten-3'one and 6-fluoro 115,175 dihydroxy 17a (a-isopropallyl)-19- nor-4-androsten-3-one are produced in the same manner as in Example 1C by dissolving 6-fluoro-115,175-dihydroxy 17 oz allyl-19-nor-4-androsten-3-one, 6-fiuoro- 115,175-dihydroxy-17a-(a-ethallyl)-19 nor-4-androsten- 3 -one, 6-fluoro-1 15,175-dihydroxy-17a-(oz-propallyl)-19- nor-4-androsten-3-one and 6-fluoro-115,175-dihydroxy- 17w(ot-isopropallyl)-19-nor-4-androsten-3-one in the appropriate 'acid anhydride and heating, for example, at between and degrees centigrade. The crude ester is isolated and crystallized in accordance with the procedure in Example 1C.

EXAMPLE 3 A. 6-flu0r0'1 5-Izydroxy-1 7 oc- (a-methallyl -4-androsten-.

3,11-dione milliliters of acetic acid there is added a solution of 0.25

gram of chromic anhydride, one milliliter of water, and twenty milliliters of acetic acid. The reaction mixture after being allowed to stand at approximately 25 degrees Centigrade for several hours is diluted with five milliliters of methanol and concentrated almost to dryness in vacuo and the residue thus obtained is then treated with The product is recovered by filtration, washed with water, dried and recrystallized from acetone-hexane to give 6a-fluoro-175-hydroxy-17a- (u-methallyl)-4-androstene-3,1l-dione, a crystalline solid. In like manner 65-fiuoro-l75-hydroxy-l7a-(a-methallyl)- 4-androstene-3,11-dione is obtained by the oxidation of 65-fluoro-1 l 5, 1 75-dihydroxy-17 cca-methallyl -4-androstene-3-one.

Similarly, 6-fluoro-175-hydroxy-l7a-allyl-4-androstene- 3,1 l-dione, 6-fluoro-175-hydroxy-17u-(a-ethallyl) -4-androstene-3,11-dione, 6- iuoro--hydroxy-17a-(u-propallyl)-4-androstene-3,1l-dione and 6-fluoro-175-hydroxy- 17 u-(a-isopropallyl)-4-androstene-3,1 l-dione are obtained in the same manner as in Example 3A by the oxidation of the corresponding starting steroid.

B. 6-flu0ro-1 7 5-hydr0xy-1 7ot- (a-methallyl -4-andrastene- 3,11-di0ne 1 7-propi0nate A solution containing one gram of 6ot-fiuoro-175-hydroxy-17a-(a-methallyl)-4-androstene-3,ll-dione in nine milliliters of propionic anhydride is heated at a temperature of approximately 100 to 150 degrees centigrade until the reaction is substantially complete. The unreacted propionic anhydride is then removed by distilling the reaction mixture under reduced pressure and the residue is crystallized from aqueous methanol to give 6a-fluoro-l75-hydroxy 17a (ix-methallyl)-4-androstene- 3,11-dione 17-propionate. Treating 65-fluoro-175-hydroxy-17a(a-rnethallyl) 4 androstene-3,11-dione with propionic anhydride as above is productive of 65-fluoro- 175-hydroxy-17a-(a methallyl)-4-androstene-3,1l-dione 17-propionate.

In the same manner shown above other 17-acylates of 6-fluoro 175 hydroxy-17u-(a-methallyl)-4-androstene- 3,11-'dione, for example, 6-fluoro-175-hydroxy-17a-(amethallyl) -4-androstene-3,1 l-dione 17-cyclopentylpropi onate, 6-fluoro-175-hydroxy-17a-(a-methallyl)-4-androstene-3,11-dione 17-acetate, 6-fluoro-175-hydroxy-17u-(umethallyl)-4-androstene-3,ll-dione 17-butyrate, 6-fluoro- 175-hydroxy-17a-(u methallyl)-4-androstene-3,1l-dione 17-valerate, 6-fluoro-175-hydroxy-17a-(a-methal1yl)-4- androstene-3,11-dione 17-hexanoate, 6-fluoro-175-hyrate,

tene 3,11 dione 17-trimethylaeetate, 6-fiuoro-17fi-hy droxy-l7a-(a-methallyl)-4-androstene-3,1l-dione 17-isobutyrate, 6-fluoro-17/3-hydroxy-17a-(a-methallyl)-4-androstene-3,l1-dione 17-isovalerate, 6-fluoro-l7fi-hydroxyl7a-(a-methallyl)-4-androstene-3,l l-dione 17-cyclohexane-earboxylate, G-fluoro-l7B-hydroxy-17a-(u-methallyl)- 4-androstene-3,1l-dione 17-benzoate, 6-fluoro-l7fl-hydroxy-l7u-(a-methallyl)-4-androstene 3,11 dione l7- phenylacetate, 6-fiuoro-17fi-hydroxy-l7ot-(u-rnethallyl)-4- androstene-3,ll-dione 17-(B-phenylpropionate), 6-fluorol7/8-hydroxy-l7a-(a-rnethallyl) 4 androstcne-3,1l-dione 17-o-, m-, p-toluate, 6-fluoro-l7p-hydroxy-17a-(amethallyl)-4-androstene-3,1l-dione l7-hemisuccinate, 6- iluoro-l7fl-hydroxy 17o: (c methallyl)-4-androstene- 3,1l-dione l7-hemiadipate, 6-fiuoro-l7fi-hydroxy-l7a-(amethallyl)-4-androstene-3,1l-dione l7-acrylate, 6-fluorol7fl-hydI'OXy-17fl-(Ot methallyl)-4-androstene-3,1l-dione l7-crotonate, 6-fluoro-17,9-hydroxy-17et-(a-methallyl)-4- androstene-3,ll-dione l7-undecylenate, 6-fluoro-l7p3-hydroxy-l7m-(m-methallyl)-4-androstene-3, l l-dione l7-propiolate, 6-lluoro 17,8 hydroxy-17a-(tx-methallyl)-4-androstene-3,1l-dione l7-cinnamate, 6-fluoro'l7B-hydroxyl7a-(a-methallyl)-4-androstene 3,11 dione l7-maleate, and G-fluoro 17,8 hydroxy-l7a-(a-methallyl)-4-androstene-3,ll-di0ne 17-citraconate, are prepared by dissolving 6-fluorol 7,3-hydroxyl 7eot-methallyl) -4-androstene- 3,11-dione in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated in accordance with the procedure above and recrystallized to give the 6-fiuoro- 17fi-hydroxy-l7a-(cz methallyl)-4-androstene-3,1l-dione l7-acylate. If the corresponding acid anhydride is solid, an inert solvent such as toluene, xylene, or dioxane can be added to effect solution and to provide a liquid esterification medium.

The l7-propionates of 6-fiuoro-l7,8hydroxy-l7a-allyl- 4-androstene-3,i l-dione, 6-fiuoro-l7 8-hydr0xy-l7u-(a ethallyl)-4-androstene-3,ll-dione, 6-liuoro-l7/3-hydroxyl7a-(u-propallyl)-4-androstene-3,ll-dione and 6-iluoro- 17/i-hydroxy-l7a-(a-isopropallyl) -4-androstene-3,l l-dione are obtained in the same manner as in Example 38 by treating the corresponding steroid with propionic anhydride. Other l7-acylates of 6-ilucro-l7,8-hydroxy-l7aallyl-iandrostene-3,ll-dione, -fluoro'l7fl-hydroxy-l7ot- (ot-cthallyl)-4-androstcne-3,ll-dione, 6-iiuoro-l75 hydroxy-l7a-(a-propallyl)-4-androstcne-3,ll-dione, and 6- fiuoro-l7,6-hydroxy-l7tx-(a-isopropallyl)-4-androstene 3, ll-dione, are produced in the same manner as in Example 33 by dissolving o-iiuoro-lm-hydroxy-l7a-allyl-4- androstene-3,l l-dione, 6-tiuorol 7/3-1ydroxy-l7a-(wethallyl)-4-androstenc-3,ll-dione, 6-flnoro-l7;3-hydroxy-l7a- (ct-propallyl)-4-androstene-3,1l-dione, and 6-fiuoro-l7t3- hydroxy-l7a-(a-isopropallyl)-4-androstene-3,ll-dione, in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated and crystallized in accordance with procedure of Example 3B.

EXAMPLE 4 12 and 6-fluoro-17/3-hydroxy-l7a-(e-isopropallyl)-l9-nor-4- androstene-3,1ldione, are obtained in the same manner as in Example 3A by oxidation of the corresponding starting steroid.

In the same manner shown in Example 38, treating 6u-fiuoro-17B-hydroxy-17a-(a-methallyl)-l9-nor 4 androstene-3-1l-dione with propionic anhydride is productive of 6a-tluoro-l7/3-hydroxy-l7a-(m-methallyl)-l9-nor- 4-androstene-3,ll-dione l7-propionate. In like manner GB-fiuoro-l7fl-hydroxy-l7a-(a-methallyl)-l9 nor 4- androstene-3,11-dione l7-pr0pi0nate is obtained by esterifying 6 3-fiuoro-1713-hydroxy-17ot-(ot-rnethallyl)-l9-nor-4- androstene-3,l1-dione with propionic anhydride.

Similarly other l7-acylates are prepared by dissolving 6-fiuoro-l7p-hydroxy-l7ot-(a-methallyl)-19-nor 4 androstene-3,ll-di0ne in the appropriate acid anhydride, heating, for example, at between and degrees centigrade and isolating the product as shown in Example 3B.

The l7-propionates of 6-tluoro-l7fi-hydroxy-l7a-allyll9-nor-4-androstene-3,l l-dione, 6-fluoro-17/3-hydroxyi7a-( a-ethallyl) -l9-nor-4-androstene-3.l l-dione, 6-iluorol7fl-hydroxy-17a-( wpropallyU-l9-nor-4-androstene-3,l 1- dione, and 6-fiuoro-l7/3-hydroxy-l7a-(wisopropallyl)-19- nor-4-androstene-3,ll-dione, are obtained in the same manner as in Example 38 by treating the corresponding steroid with propionic anhydridc. Other l7-acylates of 6-lluoro-l7B-hydroxy-l7a-allyl-l9-nor-4-androstene 3,11- dione, 6-iluoro-i7B-hydroxy-17ot-(a-ethallyl)-l9-nor-4-androstene-3,ll-dione, 6-iiuoro-l7fl-hydroxy-i7a-(a-propallyl)-l9-nor-4-androstene-3,ll-dione, and 6-fluor0-l7fihydroxy-l7a-(a-isopropallyl)-l9-nor-4-androstene 3,11- dione are produced in the same manner as in Example 38 by dissolving 6-fluoro-l7,8-hydr0xy-l7a-allyl-19-nor- 4-androstene-3, l l-dione, 6-fluoro-l7B-hydroxy-l7a-(aethallyl)-l9-nor-4-androsten3,ll-dione, 6-fiuoro-l7fi-hydroxy-l7a-(a-propallyl)-19-nor-4-androstene-3,ll dione, and 6 fluoro-l'lfX-hydroxy-l7ot-(a-isopropaliyl)19-nor-4- androstene-3,ll-dione in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated in accordance with procedure in Example 3B.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 1. A compound of the formula:

OR: --CH-CH=CH: R I 0 i wherein R is selected from the group consisting of hydrogen and methyl, R is selected from the group consisting of hydrogen and an alkyl radical containing from one to three carbon atoms, inclusive, R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and X is selected from the group consisting of CHOH and C=O.

2. 6 fiuoro 11,6,17/8 dihydroxy 17oz (a methallyl) 4 androsten 3 one.

3. 6m fluoro 115,175 dihydroxy 17a (a methallyl) 4 androsten 3 one.

4. 6 fiuoro 113,173 dihydroxy 17oz (a methallyl)-4-androsten 3-one 17-acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

5. 6a fluoro 115,176 dihydroxy 17oz (a methallyl) 4 androsten 3 one 17-acy1ates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

6. 6a fluoro 1118,1713 dihydroxy 17a (a methallyl) 4 androsten 3 one 17 propionate.

7. 6 fluoro 17 6 hydroxy 17o: (a --methallyl)- 4-androstene-3,11-dione. 1

8. 6o: fluoro 1718 hydroxy 17oz (a methallyD- 4-androstene-3,1 l-dione.

9. '6 fluoro 17,3 hydroxy 17ot (a metha1lyl) 4-androstene-3,11-dione 17-acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

10. 6a fluoi'o 17,9 hydroxy 17a (a methallyl)- 4-androstene-3,11-dione 17-acy1ates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

14 I 11. 6a fiuoro 17p hydroxy 17a (it medially!)- 4-androstene-3,11-dione 17 propionate. 12. A compound of the formula:

A R: N V

wherein R is selected from the group consisting of methyl and hydrogen and R is an alkylene group containing less than nine carbon atoms and having a four to five carbon atom bridge between the valences which, together with the nitrogen atom, forms a ring which contains from five to six members, inclusive.

13. 6 fluoro 11p hydroxy 3 (N pyrro1idinyl)- 3,5-androstadien l 7 one.

No references cited.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,888,491 June 10, 1958 Milton E. Herr et 81.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, Formula Ia, lower left-hand portion thereof should appear as shown below instead of as in the patent Signed and sealed this 7th day of October 1958.

[SEAL] Attest: KARL H. AXLINE, I ROBERT C. WATSON,

Attesting Ofiicer. S Gammissz'oner ofPatents. 

1. A COMPOUND OF THE FORMULA: 